Introduction to Liver Transplant Immunology

Jaeseok Yang, M.D., Ph.D. Transplantation Center, Seoul National University Hospital

Transplantation Research Institute, Seoul National University

Immunity vs. Tolerance

Self

Nonself Immunity

Tolerance

PRR TCR

Thymic negative selection

Regulation

Antibody

Self or Nonself ?

Tolerance vs. Accommodation vs. Rejection

• Rejection − Spontaneous immune response to allograft

• Accommodation – No harmful immune attack despite the presence of antibodies

• Tolerance – Absense of donor-reactive immune cells and antibodies

• Induction of donor-specific tolerance – Acceptance of allograft – Without further immunosuppression – With intact immune response to other foreign antigens

From Alloantigen Recognition to Graft Destruction

Secondary lymphoid organs

Antigen presentation

Migration of donor-derived and recipient-derived dendritic cells

Migration of activated T cells and antibodies

B

T Activated

T cells

Memory B cells and plasma cells

Tissue destruction

T

B

Resolution

T cell Activation

Effector Phase

Step I : Antigen Presentation in TPL

Direct presentation Indirect presentation

Semidirect presentation

Importance of MHC (HLA)

• MHC-restriction – T cells recognize self MHC plus foreign peptide, not

peptide alone – T cell receptor reacts with one antigen in combination

with one MHC molecule

Mechanisms of Direct Allorecognition

• Allorecognition of donor as an altered self – Recipient MHC-restricted TCRs recognize (donor MHC + donor peptides) as (recipient MHC + donor peptides)

• High alloreactive precursor frequency – Up to 2% of T cells vs. peptide specific T cells (1/105~1/106)

Revised from Cellular and Molecular Immunology, 5th edition

Dendritic Cells As a Professional APC

• ‘Sentinel’ to detect signs of ‘danger’ or ‘nonself’ – Pattern recognition receptor : induce the maturation of DC

• Upregulate MHC, costimulatory molecules (CD80, CD86, CD40) • Induce of chemokine receptors (CCR7) • Secrete cytokines (IL-6, IL-12, TNF-α, type I interferon)

• ‘Messenger’ to induce cellular activation

Donor Tolerogenic DC in Transplantation

T Cells Play A Key Role in Rejection

T deficient

T cells

T deficient

Step II : T Cell Activation in TPL 2 signal model : Signal 1 + 2 (positive vs. negative)

Bishop GA et al. Transplantation

2011; 91: 1065-1074

JAK-3 Inhibitor

FK778 de novo pyrimidine synthesis

T Cell Growth Factors : Signal 3

Migration : dhesion molecules & chemokines

Step III : Effector Phase of Alloimmunity

Humoral Immune Response

• Hyperacute rejection : preformed anti-donor antibody • Acute antibody-mediated rejection

– Newly formed, T cell-dependent anti-donor antibody

• Chronic antibody-mediated rejection : chronic vascular damages

Humoral Immune Response

Activation of Complement pathway

Complement- dependent tissue injury

Plasmapheresis IVIg

Splenectomy Anti-CD20 IVIg

B cell

Helper T cell

Memory B cell

Plasma cell

ATG IL-2Ab FK506 MMF

Splenectomy Bortezomib IVIg

C5 Inhibitor

Complement- independent tissue injury

B-Cell/Humoral Immunity Targeting Therapy

Innate Immune Responses

• Pattern recognition receptors : toll-like receptors – Endogeneous ligands : ischemia-reperfusion injury – Exogeneous ligands : opportunistic infection – Toll-like receptors – Contribute the rejection and interfere with tolerance

• ‘Metastable tolerance’

• Humoral effectors : complements – Classic pathway : C4d deposition in humoral rejection – Local C3 production : costimulation for APC-T interaction

Sachs SH, Nat Med, 2002

– Role of DAF & alternative pathway in APC-T interaction Heeger PS, Medof ME, JEM, 2007

Interaction between Innate & Adaptive Immunity

• Cellular effectors – Neither sufficient nor necessary – Neutrophil & macrophage : earlier infiltration to grafts – NK cells : role in rejection in CD28-/- recipients Pfeffer K, Nat Med, 2001

• Two main roles of innate immunity in rejection – Efficient antigen presentation to T cells – Effector functions under the lead of adaptive immunity (T cells)

• Phagocytosis, killing; ROS; cytokines or chemokines

Classification of Rejection of Transplantation

• Hyperacute : a preformed-antibody mediated response • Acute T-cell mediated rejection • Chronic – multifactorial

– immune factors – nonimmune factors

0 1 6 12 24 Post-TPL time (months)

Rel

ativ

e R

isk

hyperacute acute chronic

Step IV : Resolution of Immunity in TPL

• Resolution of allograft rejection – Apoptosis of donor-reactive T & B cells - Generation of memory T & B cells/preformed antibodies

• Accelerated rejection – Retransplantation with the sensitized alloantigens

Accelerated Rejection in Second-set TPL

Regulatory Cell Population

• Naturally occuring Tregs vs. adaptive (induced) Tregs • CD4+ T cells

– CD4+CD25+ Tregs, CD103+ Tregs, CD4+CD25- Tregs – Tr1 cells: Ag-induced, IL-10+, ROG+, Granzyme A+, Foxp3- – Th3 cells : TGF-β production, Foxp3+

• CD8+ T cells – CD8+ Tregs : Qa-1 (HLA-E) restricted Treg for CD4+ T cell – IL-10 producing CD8+CCR7+ or CD8+CD122+Foxp3- Tregs – CD8+CD28-Foxp3+ T cells (human), CD8+CD25+Foxp3+

• CD4-CD8- T cells : cytotoxicity toward T cells • γδT cells • Regulatory B cells

– CD19+, CD1d+, IL-10+, CD5+, TIM-1+

Regulatory T Cells in Transplantation

• Concept of linked suppression and infectious suppression

Tolerance Dynamic Balance Between Effectors T Cells & Tregs

Rejection Tolerance Rejection Tolerance

• Deletion – Reduce the clone size of alloreactive T cells

• Regulation – A key role in maintain a tolerance – Expansion of naïve Tregs or induction of adaptive Tregs

Tregs

Effector T cells

Induction & Maintenance of TPL Tolerance

Why Is Transplant Tolerance Hard to Achieve? Why Is Rejection the Strongest Immune Reaction?

• Very high frequency of alloreacitve T cells • Influence of innate immune response

– Weak rejection in small animal models in SPF conditions – Difficult tolerance induction in outbreed animal, non-

human primates and clinical settings

• Existence of memory T cells – Prior direct alloantigen exposure : prior transplantation,

transfusion, pregnancy – Heterologous immunity – Homeostatic proliferation

Mechanisms of Weaker Rejection in Liver TPL

• Production of donor-strain soluble MHC I by liver • Soluble HLA-G in LT and SLK inhibits T, NK, and DCs. Transplant Immunology Volume 17, Issue 2, 98–107 • Donor-derived microchimerism by passenger stem cells • Mass effects, AICD, IDO etc.

Orlando G et al, J Hepatol 2009;50:1247-1257

• Endotoxin tolerance: dendritic cells, kupffer cells, sinusoidal endothelial cells, and hepatocytes lead to tolerization of T cells – Tolerance can be reversed by infection

• Innate immunity such as NK and NKT cells – Anti-HCV specific T cells do not induce rejection Gastroenterology. 2011 Jan;140(1):51-64

Clinical Operational Tolerance in Liver TPL Tolerance development in 20% of liver TPL

Remove immunosuppressants in nonimmunologic original liver disease Rejection can be reversed by steroid pulse therapy Liver damage can be repaired easily by regeneration